Opioid receptors are an important G protein-coupled receptor (GPCR), and are the target of a combination of endogenous opioid peptides and opioid drugs. The activated opioid receptors play a regulatory role in immunity of the nervous system and endocrine system. Opioid drugs are the strongest and most commonly used central analgesics. Endogenous opioid peptides are naturally occurring opioid-like active substances in mammals. Currently, the known endogenous opioid peptides can be roughly divided into enkephalin, endorphin, dynorphin and nociceptin (Pharmacol. Rev. 2007; 59: 88-123). There are corresponding opioid receptors in the central nervous system, i.e., μ (MOR), δ (DOR), κ (KOR) receptors and the like. It was found that the strength of the analgesic effect of endogenous opioid peptides mainly depends on the expression level of opioid receptors. Opioid receptors are the targets of the analgesic effects of opioid drugs and endogenous opioid peptides. Zadina et al. found that the binding ability of the MOR receptor to morphine peptide 1 is strongest (360 pM). It's 4000 times that of the binding of the DOR receptor to morphine peptide 1, and 15000 times that of the binding of the KOR receptor to morphine peptide 1. The MOR receptor is the most important opioid receptor for mediating analgesic effects (Science, 2001, 293: 311-315; Biochem. Biophys. Res. Commun. 235:567-570; Life Sci. 61:PL409-PL415).
The current studies suggest that GPCR mediates and regulates physiological functions mainly through two pathways: the G protein signaling pathway and the β-arrestin pathway. The G protein signaling pathway can be activated by the binding of the traditional GPCR agonist to the receptor, and includes the second messenger system such as calcium ion, adenyl cyclase (AC), mitogen-activated protein kinases (MAPK) and the like. In contrast, the β-arrestin pathway is mainly activated by a β-arrestin-biased ligand. The β-arrestin mediated GPCR response mainly includes three aspects: 1) β-arrestin as a negative regulator reacts with the G protein-coupled receptor kinase (GRK), thereby causing receptor desensitization in GPCRs, and blocking of the transduction of G protein signaling; 2) β-arrestin as a scaffold protein recruits the endocytic protein and induces the endocytosis of GPCR; and 3) β-arrestin as an adapter protein forms a complex with GPCR downstream signaling molecules, and activates the signal transduction molecules, such as MAPK, Src protein tyrosine kinase and Akt, etc., in a G protein independent manner. The differences of ligand stimulation on G protein signaling and/or β-arrestin signaling ultimately determine the ligand-specific cellular biological effects of GPCR.
MOR is the target of opioid analgesic drugs such as endogenous enkephalin and morphine. Early studies have shown that endogenous enkephalin and the opioid drug etorphine can agonize G protein and cause receptor endocytosis, but morphine cannot cause receptor endocytosis at all. This is because the agonistic activity of morphine on MOR phosphorylation is too weak, and only trace β-arrestin is recruited yo the membrane (Zhang et al., Proc. Natl. Acad. Sci. USA, 1998, 95 (12): 7157-7162). These ligands exert their physiological functions completely through the G protein signaling pathway rather than the β-arrestin pathway. The study found that after morphine is injected into β-arrestin2 knockout mice, the analgesic effect mediated by G protein signaling is stronger and the duration is longer (Bohn et al., Science, 1999). It is foreseeable that if the negative β-arrestin bias of such ligands is stronger, even they can escape the β-arrestin mediated receptor desensitization, thereby leading to longer G protein signaling durations and more potent analgesic effects.
Patent applications disclosing MOR agonists include International Patent Application Publication Nos. WO2014022733, WO2008009415, WO2009018169, WO2012129495, WO2001049650, WO2002020481, WO2010051476 and WO2013087589 and the like.
Long-term use of opioid drugs produces side effects such as tolerance, respiratory depression and constipation. Additionally, it has been demonstrated that these side effects are closely related to the function of β-arrestin. In order to reduce the side effects of opioid drugs, the drugs can be designed based on the MOR negative β-arrestin-biased ligand, thereby reducing the β-arrestin mediated side effects and enhancing the therapeutic effect. In a study of the oxo spiro derivatives of the present invention used as selective MOR drugs, Trevena Inc. has found that the activity is lower when the substituent is on the benzylic position of the aryl (J. Med. Chem. 2013, 56, 8019-8031). However, after a series of studies, the present inventor has found that the oxo spiro derivatives have high activity after the benzylic position is cyclized, the Emax was significantly improved, hERG was significantly improved, and further studies found that the compound with a single configuration has a higher selectivity for the MOR.